Effect of RX 821002 at 5-HT1A-receptors in rabbit spinal cord in vivo.

1. The activity of RX 821002 (2-methoxy idazoxan) at 5-HT1A-receptors in the spinal cord has been investigated in decerebrated, spinalized rabbits. Reflexes evoked in medial gastrocnemius motoneurones by electrical stimulation of the sural nerve were unaffected by intrathecal (i.th.) administration of RX 821002 (111 and 664 nmol cumulative, n = 7), although the highest dose of this drug did produce a significant increase in heart rate of 28 +/- 7 beats min(-1). Subsequent administration of the 5-HT1A-receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 300 nmol, i.th., facilitated reflexes to a median of 144% of pre-drug controls, an effect that was partially reversed (to a median value of 120% of pre-drug values) by subsequent administration of the 5-HT1A-receptor antagonist WAY-100635, at 185 nmol i.th. 2. In a separate set of experiments, 8-OH-DPAT was given at 30 nmol i.th. and potentiated reflexes to a median of 170% of pre-drug levels (n = 8). Subsequent administration of RX 821002 (at a cumulative dose of 1.11 micromol, i.th., n = 5) significantly reduced gastrocnemius responses to a median of 154% of control values. 3. After a 3 h recovery period, 8-OH-DPAT was re-administered at 30 nmol, i.th., and increased reflexes to a median value of 151% of pre-drug levels, an effect not significantly different from when it was given alone. WAY-100635 dose-dependently antagonized this effect, causing significant reductions in reflexes at a cumulative dose of 0.55 nmol, i.th., and complete reversal of the effects of 8-OH-DPAT at a cumulative dose of 5.5 nmol. 4. These data show that, at intrathecal doses up to 664 nmol, RX 821002 is devoid of agonist activity at 5-HT1A-receptors. It appears to be a very weak antagonist at these sites in vivo, being some 2000 times less potent than WAY-100635. The inability of WAY-100635 to block completely the effects of high doses of 8-OH-DPAT has been noted previously and can be explained by non-selective actions of the agonist. However, it would appear that a 30 nmol i.th. dose of 8-OH-DPAT is selective for 5-HT1A receptors in this preparation.